Cancers are caused by multiple genetic changes that drive tumorigenesis. Over the past several years, overexpressed oncogenic targets such as receptor tyrosine kinases (RTKs) have been targeted for treatment of cancers. Cancers can also arise from the loss of tumor suppressor gene functions such as through the loss of p53, BRCA1, BRCA2, PTEN and other tumor suppressor genes. Currently no therapeutic approaches have been designed to target cancers that are due to the loss of tumor suppressor gene functions.
The concept of synthetic lethality was introduced, recently, into the field of cancer therapeutics. Initial research in the field of synthetic lethality indicated that two genes are synthetic lethal if mutation of either gene alone is compatible with viability but a mutation of both genes results in cell death. There have been recent examples of treatment of cancers that have a BRCA1 gene deficiency by administration of a DNA crosslinking agent, such as a platinum drug, in combination with an inhibitor of an overexpressed gene, such as PARP, to produce a synthetic lethal outcome in such BRCA1 deficient tumor cells (A. Ashworth: A synthetic lethal therapeutic approach: Poly(ADP) Ribose Polymerase Inhibitors for the Treatment of Cancers Deficient in DNA Double-Strand Break Repair. J Clinical Oncology 26:3785-3790, 2008; Rehman, F. L., Lord, C. J. and Ashworth, A. Synthetic lethal approaches to breast cancer therapy. Nat Rev Clin Oncol 7: 718-724, 2010; O'Shaughnessy, J., Osborne, C., Pippen, J. E., Yoffe, M, Patt, D., Rocha, C., Koo, I. C., Sherman, B. M. and Bradley, C. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 364: 205-214, 2011.
Currently, labor intensive bioinformatic analysis and small molecule or RNAi screens are needed to identify synthetic lethal relationships between well-established therapeutic targets and/or lesser-known components of cancer cells' signaling networks.
At present, the only clinical application of synthetic lethality is the use of DNA crosslinking platinum drugs such as carboplatin, together with an antimetabolite such as gemcitabine, in combination with poly (ADP-ribose) polymerase (PARP) inhibitor, such as iniparib in patients with triple-negative breast cancer that have BRCA1 and/or BRCA2 mutations (O'Shaughnessy et al., N Engl J Med 364: 205-214, 2011). Preclinical studies were required to establish synthetic lethal relationships among the combination of a DNA crosslinking agent (platinum), and antimetabolites (gemcitabine) and the inhibition of the DNA repair enzyme PARP, together with the genetic inactivation of tumor suppressor genes BRCA1 or BRCA2.
A clear advantage of cancer treatments based on synthetic lethality is that they have minimal toxicity, because only cells with the impairments that comprise the synthetic lethal relationship (e.g., a mutated gene and a therapeutically inhibited enzyme) should be affected. Those cells should almost exclusively be cancer cells. Treatments based on synthetic lethality offers the advantage of overcoming the problem of targets that, either due to underlying biology or the targets' actual physical make up, are “undruggable” with small molecule and biologic drugs. As much as 75% of the identified molecular targets for cancer may be “undruggable”.
A key obstacle to appropriate treatment of cancers and other inflammatory diseases is the resistance or refractory responses to available therapies. For example, it is well known that tumor cells develop mutations in various genes and/or their expressed proteins. Such mutations allow the tumor cells to become refractory to currently available anticancer agents and thus the patients do not have therapeutic options. The novel invention described in this application shows the benefit of using non-covalent DNA binding agents that show synthetic lethality in tumors that carry mutations, particularly in DNA repair or tumor suppressor genes, that result in a “loss of function” in the cell's ability to either repair itself or go into apoptosis or programmed cell death. Since such mutations in DNA repair or tumor suppressor genes also render the tumor cells refractory to available treatments, the novel combinations of one or more non-covalent DNA binding agents with one or more anticancer or anti-inflammatory agents, represents a novel and unique way to treat tumor cells that have “loss of function” in tumor suppression and/or DNA repair functions.
Furthermore, in view of the fact that a) it is difficult to identify and/or predict synthetic lethal relationships, and b) the importance of cancer treatments based on synthetic lethality, there is a real and immediate need for methods of disease treatment based on combinations of agents that can leverage synthetic lethality and to develop such novel combinations in a rapid time frame, so that it does not involve time consuming identification of synthetic lethal relationships amongst genes. Moreover, such novel compositions of agents should result in treatment methods that are non-toxic. This application describes unique and novel compositions of combinations or one or more non-covalent binding DNA agents with one or more available anticancer agents, including but not limited to, those agents that have become refractory due to mutations in such cells and provide novel methods of therapies for treatment of highly unmet clinical need in cancer and inflammatory diseases, while leveraging, the concept of synthetic lethality.